Our overall objective is to dissect the role of the steroid receptor coactivator (SRC-1) family in governing the tissue-selective physiological functions of estrogen (E) and progesterone (P) as mediated through their cognate nuclear receptors, ER and PR, respectively. Our working hypothesis is that ER and PR act in the female reproductive system and mammary gland via obligatory interactions with SRC family members, which determine their actions in a developmental-, tissue-, gene-, receptor-, and ligand-specific manner. This hypothesis will be tested in the following Specific Aims: Specific Aim 1 will employ conditional murine transgenic approaches to selectively increase SRC expression to disclose the involvement of each SRC in a given ER- and/or PR-mediated physiological response. To address the proposed functional synergy between SRC-1 and SRC-2 in the adult, Specific Aim 2 will utilize CRE/loxP engineering strategies to conditionally ablate SRC-2 function in the SRC-1 knockout mouse; the SRC-1/SRC-2 double knockout results in early postnatal lethality. Specific Aim 3 will use existing PRA, PRB and SRC knockout mouse models to define the SRC contributions to the tissue-selective effects elicited by these PR isoforms in vivo. This aim will also employ the three SRC knockout mouse models (and combinations thereof) to address the fundamental basis of the specific effects of natural ligands and selective receptor modulators (SRMs). Specific Aim 4 will co-opt state-of-the-art ultrastructural, histological, and molecular approaches to phenotypically characterize the animal models described in this proposal. These studies are essential not only to further understand the tissue-specific biology of SRC family members, but will pave the way for a greater comprehension of the mode of action of SRMs that will improve prospects for their therapeutic application in the myriad of endocrine disorders in which nuclear receptors, and by association SRCs, are implicated.